US5541183A - Ginkgolide derivatives - Google Patents

Ginkgolide derivatives Download PDF

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US5541183A
US5541183A US08/366,594 US36659494A US5541183A US 5541183 A US5541183 A US 5541183A US 36659494 A US36659494 A US 36659494A US 5541183 A US5541183 A US 5541183A
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ginkgolide
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benzyloxy
carbon atoms
methoxy
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Pyeong-Uk Park
Sungsoo Pyo
Suk-Kwan Lee
Jin H. Sung
Wie J. Kwak
Hwa-Kun Park
Yong-Baik Cho
Geun Ho Ryu
Taek S. Kim
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SK Discovery Co Ltd
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Sunkyung Industries Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D493/00—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system
    • C07D493/22—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system in which the condensed system contains four or more hetero rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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    • A—HUMAN NECESSITIES
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    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
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    • A—HUMAN NECESSITIES
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    • A—HUMAN NECESSITIES
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    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/06—Antiasthmatics
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    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/08—Bronchodilators
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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    • A—HUMAN NECESSITIES
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    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/06—Antipsoriatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61P37/02—Immunomodulators
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    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/08—Antiallergic agents
    • A—HUMAN NECESSITIES
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    • A—HUMAN NECESSITIES
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    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/04—Antihaemorrhagics; Procoagulants; Haemostatic agents; Antifibrinolytic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/06—Antiarrhythmics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis

Definitions

  • the present invention relates to new ginkgolide derivatives of formula (I), which have valuable PAF-antagonistic activity, and a process for preparing them, including a process for preparing Ginkgolide B derivatives and the pharmaceutical use of the derivatives. These compounds have excellent physiological activity. ##STR2##
  • Benveniste et al. found a factor in 1972 which strongly induced platelet aggregation from rabbit basophils. This factor was named platelet-activating factor (hereinafter referred to simply as PAF).
  • PAF platelet-activating factor
  • Hanahan et al. identified the factor in 1980 as a phosphoglyceride of the alkyl ether type having an acetyl group in the 2-position, i.e. 1-O-hexadecyl or octadecyl-2-acetyl-sn-glyceryl-3-phosphorylcholine.
  • PAF PAF protein oxidative stress oxidation
  • various physiological reactions including platelet aggregation, reduction in blood pressure, immediate allergic reaction, contraction of smooth muscle, inflammation, pain, edema, and alteration in the respiratory and circulatory systems.
  • PAF-antagonistic activity-possessing compounds are very useful for treating various PAF-induced diseases, such as inflammatory diseases, allergic diseases, anaphylatic shocks, septic shocks, vascular diseases as DIC, myocardinal diseases, asthma, pulmonary edema, and adult respiratory diseases.
  • ginkgolide compounds (A, B, C, M and J), which are terpenoid compounds from the roots and leaves of the Ginkgo tree, have exhibited the PAF antagonistic activity described above.
  • these compounds possess certain deficiencies in the areas of effects on the central nervous system, potency, effectiveness by oral administration, water solubility, effectiveness by intravenous administration and duration of activity. Therefore, there is a need for potent PAF-antagonistic ginkgolide compounds which possess not only effectiveness by oral administration, long lasting effect, water solubility and effectiveness by intravenous administration, but also less inhibitory effects on the central nervous system.
  • the present inventors have conducted long term investigations and studies on ginkgolide derivatives which have not only excellent PAF-inhibiting activity, but also excellent physiological activity.
  • the present invention has been accomplished based on these findings.
  • the present invention is directed to new ginkgolide derivatives, methods of preparing them and their pharmaceutical uses. Additional features and advantages of the invention will be set forth in the description which follows, and in part will be apparent from the description or may be learned from practice of the invention. The advantages of the invention will be realized and attained by the compounds and processes particularly pointed out in the written description and claims.
  • the invention provides new ginkgolide derivatives, which may be used for the prevention or treatment of various PAF-induced diseases, and the pharmaceutical uses of these derivatives. There is also provided a process for preparing these ginkgolide derivatives.
  • the present invention relates to the new ginkgolide derivatives of the formula (I): ##STR3## wherein R 2 represents hydrogen or an R 1 group, and
  • R 1 represents --A--Ar, --A--Z--Ar, ##STR4## --SO 2 --Ar, --A--Het. or --A--NR 4 R 5 , in which
  • A represents an alkylene group having 1 to 8 carbon atoms, which is unsubstituted or substituted by a straight or branched alkyl chain having 1 to 5 carbon atoms,
  • Z represents carbon, oxygen, sulfur or nitrogen
  • Ar represents a phenyl group, a pyridyl group, a naphthyl group, a pyrimidyl group, or a quinolyl group, each of which is unsubstituted or substituted by one to five substituents selected from the group consisting of hydrogen, a halogen atom, a hydroxy group, a carboxylic acid group, an alkyl group having 1 to 10 carbon atoms, an alkenyl group having 1 to 10 carbon atoms, an alkynyl group having 1 to 10 carbon atoms, a haloalkyl group having 1 to 10 carbon atoms, an alkoxy group having 1 to 10 carbon atoms, an alkenyloxy group having 1 to 10 carbon atoms, an alkynyloxy group having 1 to 10 carbon atoms, a haloalkoxy group having 1 to 10 carbon atoms, a phenyl group, a phenoxy group, an aralkyl group, an aral
  • Het. represents a cyclic saturated or unsaturated heterocyclic group having one or more nitrogen, oxygen, and/or sulfur atoms
  • R 4 R 5 represent the same or different and each is hydrogen, an alkyl group having 1 to 10 carbon atoms or a cycloalkyl group having 3 to 10 carbon atoms.
  • the present invention relates to the process for preparing the new ginkgolide derivatives of formula (I).
  • the compounds of formula (I) can be prepared by reacting a compound of formula R 1 -L and the known Ginkgolide B of formula (II) in the presence of bases and organic solvents. ##STR5##
  • R 1 and R 2 are as defined above, and L represents a halogen atom (for example, fluorine, chlorine, bromine or iodine), 4-metylbenzenesulfonyloxy, methanesulfonyloxy, 4-nifrobenzenesulfonyloxy, 4-bromobenzenesulfonyloxy or trifiuoromethanesulfonyloxy.
  • halogen atom for example, fluorine, chlorine, bromine or iodine
  • 4-metylbenzenesulfonyloxy methanesulfonyloxy
  • 4-nifrobenzenesulfonyloxy 4-bromobenzenesulfonyloxy or trifiuoromethanesulfonyloxy.
  • the present invention relates to the process for preparing the new ginkgolide derivatives of formula (I') by reacting a compound of formula (III) with a compound of formula Q-H. ##STR6##
  • A is as defined above
  • Q is Het. or NR 4 R 5 (in which Het., R 4 and R 5 are as defined above)
  • X represents a halogen atom (fluorine, chlorine, bromine or iodine).
  • the compounds of the above formula (III) can be prepared by reacting a compound of formula (IV) and the known Ginkgolide B of formula (II) in the presence of bases and organic solvents. ##STR7##
  • Y represents 4-methylbenzenesulfonyl, methanesulfonyl, 4-nitrobenzenesulfonyl, 4-bromobenzenesulfonyl, or trifluoromethanesulfonyl.
  • R 1 and R 2 in the above formula (I) are as shown below:
  • R 2 represents hydrogen or an R 1 group
  • R 1 represents --A--Ar, --A--Z--Ar, --CO--Ar, --SO 2 --Ar, --A--Het. or --A--NR 4 R 5 in which A represents an alkylene group having 1 to 8 carbon atoms, for example, methylene, ethylene, trimethylene, tetramethylene, pentamethylene, hexamethylene, heptamethylene or octamethylene group, which is unsubstituted or substituted by a straight or branched chain alkyl group having 1 to 5 carbon atoms, such as methylmethylene, propylene, methyltrimethylene, dimethylethylene, dimetyltetramethylene, ethylethylene or dimethyltrimethylene;
  • Z represents carbon, oxygen, sulfur or nitrogen;
  • Ar represents a phenyl group, a pyridyl group (including, for example, 1-pyridyl, 2-pyridyl, 3-pyridyl and 4-pyrid
  • a saturated or unsaturated heterocyclic group having one or more nitrogen, oxygen, and/or sulfur atoms for example, morpholinyl, piperidinyl, piperazinyl, triazolyl, imidazolyl, pyrrolidyl, thiazolidinyl and furanyl.
  • substituteduents in Ar includes hydrogen; halogen, including, for example, fluorine, chlorine, bromine or iodine; a hydroxy group; a carboxylic acid group; an alkyl group having 1 to 10 carbon atoms, including, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, 1-methylbutyl, n-hexyl, 1-methylpentyl, n-heptyl, 4-methylhexyl, 1-ethylpentyl, 1,4-dimetylpentyl, n-octyl, 6-methylheptyl or 2-ethylhexyl; an alkenyl group having 1 to 10 carbon atoms, including, for example, vinyl, allyl, 3-pentenyl or 1-hex
  • Particularly preferred compounds of the present invention are the compounds of formula (I) wherein R 2 is hydrogen, and R 1 is --CH 2 --Ar, --CH 2 --CH 2 --Ar, --CH 2 CH 2 CH 2 --Ar, --CH 2 O--Ar, --CH 2 CH 2 O---Ar, --CH 2 CH 2 CH 2 O--Ar, ##STR8## or --SO 2 --Ar, in which Ar is a phenyl group, a pyridyl group, a pyrimidyl group, or a quinolyl group, each of which is unsubstituted or substituted by one to five substituents selected from the group consisting of hydrogen, halogen, a hydroxy group, an alkyl group having 1 to 10 carbon atoms, a haloalkyl group having 1 to 10 carbon atoms, an alkoxy group having 1 to 10 carbon atoms, a haloalkoxy group having 1 to 10 carbon atoms, a phenyl group, a
  • More particularly preferred compounds of the present invention are the compounds selected from the group consisting of
  • the present invention further provides the pharmacological use of the compound of formula (I) defined above.
  • a pharmaceutical composition which comprises a pharmacologically effective amount of a compound of formula (I) and a pharmacologically acceptable carrier.
  • the present invention also provides a method for treating a disease against which anti-PAF activity is effective, which comprises administering a pharmacologically effective amount of a compound of formula (I) to a host in need.
  • the diseases which may be treated in this manner include allergic diseases such as asthma, inflammatory diseases, septic shock and anaphylactic shock, vascular diseases such as DIC, myocardial diseases, pulmonary edema and adult respiratory diseases.
  • This reaction is usually carried out for 1 to 10 hours at 0°-70° C. in a solvent (e.g., tetrahydrofuran, acetone, ethyl acetate, dimethyl formamide, dimethyl sulfoxide, pyridine, dioxane, methanol, ethanol, 2-methoxyethanol or a mixed solvent thereof) in the presence of an easily available base.
  • a solvent e.g., tetrahydrofuran, acetone, ethyl acetate, dimethyl formamide, dimethyl sulfoxide, pyridine, dioxane, methanol, ethanol, 2-methoxyethanol or a mixed solvent thereof
  • These easily available bases include, for example, Ag 2 O, triethylamine, an alkalicarbonate, an alkalibicarbonate, an alkali hydroxide, MH, wherein M is alkali metal such as Li, Na, K, etc. (e.g., lithium hydride, sodium hydride, potassium hydride), MNH 2 (e.g., sodium amide, etc.), MOR 4 , MR 4 , R 4 R 5 NM, MN(TMS) 2 and mixtures thereof (R 4 and R 5 are the same as defined above and TMS is trimethylsilyl group).
  • M alkali metal
  • M alkali metal
  • MNH 2 e.g., sodium amide, etc.
  • compounds of formula (III) defined above may be reacted with with a compound of formula Q-H defined above either in the presence of solvent and base or in the absence of solvent and base.
  • the reaction is usually carried out for 1 to 10 hours at 0°-90° C. in a solvent (e.g., tetrahydrofuran, acetone, ethyl acetate, dimethyl formamide, dimethyl sulfoxide, pyridine, dioxane, methanol, 2-methoxyethanol or mixtures thereof) in the presence of an easily available base (as defined above).
  • a solvent e.g., tetrahydrofuran, acetone, ethyl acetate, dimethyl formamide, dimethyl sulfoxide, pyridine, dioxane, methanol, 2-methoxyethanol or mixtures thereof
  • the compounds of the formula (I') may also be prepared from the compounds of the formula (III) and Q-H directly, i.e. in the absence of solvent and base. In this reaction, it is especially preferable to conduct the reaction at 0°-90° C. due to the slowness of the reaction below 0° C. and the presence of side reactions above 90° C., which result in low yields.
  • compounds of formula (III) may be prepared by reacting a compound of formula (II) and a compound of formula (IV) in a mixed organic solvent (as defined above) in the presence of an easily available base for 1 to 10 hours at 0°-90° C.
  • a mixed organic solvent as defined above
  • the organic solvent and base are the same as employed in the preparation of compounds of the formula (I) described above.
  • the new Ginkgolide B derivative is useful as a PAF-antagonistic agent.
  • the mixture was treated with 0.5 ml of c-HCl at 0° C., diluted with 10 ml of water and extracted with 50 ml of ethylacetate. The solution was washed with 10 ml of water and dried over anhydrous magnesium sulfate.
  • Example 97 the title compound was prepared using 160 mg of Ginkgolide B and 200 mg of 2-picolylchloride (78 mg, 40%).
  • Example 98 the title compound was prepared using 120 mg of Ginkgolide B and 200 mg of 5-butyl-2-picolyl chloride (118 mg, 74%)
  • the title compound was prepared using 55 mg of Ginkgolide B and 70 mg of 2-(iodomethyl)-quinoline (41 mg, 55%).
  • Example 98 the title compound was prepared using 115 mg of Ginkgolide B and 168 mg of 6-chloro-3-picolyl chloride (87 mg, 59%).
  • Example 98 the title compound was prepared using 200 mg of Ginkgolide B and 250 mg of 3-picolyl chloride (164 mg, 68%).
  • the titile compound was prepared using 200 mg of Ginkgolide B and 240 mg of 4-picolyl chloride (109 mg, 45%).
  • Example 104 In the same manner as in Example 104, the title compound was prepared using 10-(4-nitro-2-myridinyl)-methoxy Ginkgolide B obtained in Example 111 (85%).
  • Example 96 the title compound was prepared using Ginkgolide B and 5-(2-methoxyethoxymethoxy)-2-picolyl bromide or the mesylate of 5-(2-methoxyethoxymethoxy)-2-pyridyl carbinol (76%).
  • Example 114 To a solution of 250 mg of the compound obtained in Example 114 in 3 ml of tetrahydrofuran was added 1 ml of c-HCl followed by stirring at room temperature. After 2 hours stirring an room temperature, the mixture was concentrated under reduced pressure.
  • the mixture was treated with 0.5 ml of c-HCl at 0° C., diluted with 10 ml of water and extracted with 50 ml of dichloromethane. The solution was washed with 10 ml of water and dried over anhydrous magnesium sulfate. After filtering off, the filtrate was concentrated under reduced pressure.
  • Example 117 100 mg of 10-(2'-iodoethoxy)-Ginkgolide B obtained in Example 117 was dissolved in 2 ml of piperidine, and stirred at room temperature for 1 hour. The excess piperidine was removed under reduced pressure. The residue was subjected to chromanography on silica gel to give 57 mg (62%) of the desired compound.
  • Example 118 In the same manned as in Example 118, the title compound was prepared using morpholine (75%).
  • Compounds which have PAF-antagonistic activity may be used for the treatment and prophylaxis of diseases mediated or effected by PAF.
  • Typical diseases for which the inventive compounds may be used as a therapeutic and prophylactic agent include allergic diseases, asthma, thrombosis, cerebral apoplexy (cerebral hemorrhage, cerebral thrombosis), myocardial infarction (angina pectoris), human disseminated intravascular coagulation syndrome (DIC), thrombophlebitis, glomerular hepatitis, anaphylatic shock, hemorrhagic shock, septic shock, endotoxin shock, rheumatoid arthritis, osteoarthritis, edema, inflammation, cardiovascular disorder, adult respiratory distress syndrome, immune regulation, gastric ulceration, transplant rejection, psoriasis, allergic dermatitis, urticaria, multiple sclerosis, and other conditions in which PAF is implicated.
  • the inventive ginkgolide B derivatives have potent PAF-antagonistic activity. Accordingly, the new ginkgolide B derivatives may be used in pharmaceutical composition comprising a pharmaceutically effective amount of one of the compounds defined above and a pharmaceutically acceptable carrier. The compounds are effective for the therapy and prophylaxis of diseases mediated or effected by PAF.
  • inventive compounds are particularly useful as anti-allergic agents, anti-asthmatic agents, anti-psoriasis agents, anti-anaphylactic shock agents, anti-septic shock agents, an anti-bowel necrosis agents, an adult respiratory distress syndrome agents and anti-transplant rejection agents.
  • Compounds of formula (I) may be administered orally, topically, parenterally, by inhalation spray or rectally in dosage unit formulations containing conventional non-toxic pharmaceutically acceptable carriers, adjuvants and vehicles.
  • parenteral as used herein includes subcutaneous injections, intravenous injection, intramuscular injection, intrasternal injection or infusion techniques.
  • the dosage employed depends on the type of disease, the degree of symptom and age.
  • the dosage levels of the compound in the above-indicated compositions may, of course, be varied and may conveniently be between about 0.1% to about 95% of the weight the unit.
  • a dose of 1-50 wt. % is particularly preferred.
  • a dose of 0.1-20 wt. % is particularly preferred.
  • compositions containing compounds of formula (I) may be in any form suitable for oral use, for example, as tablets, troches, lozenges, aqueous or oily suspensions, dispensable powders or granules, emulsion, hard or soft capsules, syrups or elixirs.
  • the tablets, capsules and the like may also contain a binder, such as lactose, saccharose, sorbitol, mannitol, starch, amylopectin, cellulose or gelatin; excipients, such as dicalcium phosphate; a disintegrating agent, such as corn starch or potato starch; a lubricant, such as magnesium stearate, calcium stearate, sodium stearylfumalate or polyethylenglycol wax.
  • a binder such as lactose, saccharose, sorbitol, mannitol, starch, amylopectin, cellulose or gelatin
  • excipients such as dicalcium phosphate
  • a disintegrating agent such as corn starch or potato starch
  • a lubricant such as magnesium stearate, calcium stearate, sodium stearylfumalate or polyethylenglycol wax.
  • active compounds of formula (I) may also be administered parenterally.
  • a solution or suspension of the active compounds may be prepared in water, optionally mixed with stabilizer or buffering agents.
  • the dosages for parenteral administration are 0.1-10 wt. %, and preferably administered as ampule or vial type.
  • Dosage levels of about 2 mg to about 1,000 mg (70 kg of body weight, adult) per day are particularly useful for the prevention or treatment of allergic bronchial disease and allergic rheumatoid arthritis.
  • dosage levels of about 1 mg to about 10 mg are particularly preferred.
  • the compound of the present invention may also be administered directly to the airways, for example, in the form of an aerosol or inhalation by nebulizer, for the treatment of allergic bronchial hyperreactivity.
  • Dosage unit forms will generally contain between about 0.1 mg to about 50 mg of the active ingredient.
  • the present invention provides pharmaceutical compositions comprising a pharmaceutically effective amount of a compound of formula (I) and a pharmaceutically acceptable carrier.
  • the present invention also provides the pharmaceutical uses of these compounds and compositions, especially for treatment of allergic diseases and inflammatory diseases in humans.
  • the active ingredient represents a compounds of general formula (I), which may be substituted by any pharmaceutically effective amount of another compound of general formula (I).
  • Platelet rich plasma was obtained by centrifugation of the blood at 150 g for 10 min at room temperature. The number of platelets was adjusted to 3 ⁇ 10 8 platelets/ml with platelet poor plasma. Platelet aggregation was monitored by continuous recording of light transmission in a dual-channel aggregometer (Chrono-Log 560-VS) coupled with a two channel recorder (Chrono-Log 707). Stirred PRP was treated with various concentrations of the test compounds or vehicle (0.5% DMSO) for 2 min and then PAF(5 ⁇ 10 -9 M) was added to induce platelet aggregation.
  • PRP Platelet rich plasma
  • Inhibition values were calculated by comparing the extent of aggregation obtained in the presence of the vehicle alone (0.5% DMSO) and in the presence of a test compound. Log concentration-response curves were generated and the IC 50 values were determined by regression analysis.
  • Table 1 lists results from this assay for inhibition of PAF-induced rabbit platelet aggregation for illustrative examples of the compounds of this invention.
  • a pressure transducer Physiological Pressure Transducer, MICRON INSTRUMENT MP-15
  • COULBOURN INSTRUMENT 572-25 an amplifier
  • COULBOURN INSTRUMENT R14-18 COULBOURN INSTRUMENT R14-18.
  • the rate of bronchoconstriction was measured as an increase in lung overflow with a bronchospasm transducer (UGO BASILE 7020) from a side arm off the tracheal cannula, and expressed as a percentage of maximum bronchoconstriction obtained by clamping off the tracheal cannula.
  • Test compounds or vehicle (0.5% DMSO) were administered through the cannula into the jugular vein and PAF (100 ng/kg, i.v.) was administered. Bronchoconstriction response was compared to that obtained with control group treated with vehicle. Percent inhibition was calculated for each dose. Log dose-response curves were generated and the ID50 values were determined by regression analysis, and the results are presented in Table 2.
  • Table 2 Results for inhibition of PAF-induced bronchoconstriction in the guinea pig.
  • mice Male guinea pigs (Hartley strain), weighing 350 to 500 g. The animal was passively sensitized with rabbit anti-chicken egg albumin (1.3 mg/kg), 17-24 hrs before ovaibumin challenge. Passively sensitized animals were anesthetized with ethyl carbamate 1.5 g/kg, i.p.). An intratracheal cannula was inserted into trachea and indwelling catheters were inserted into the right carotid artery and left jugular vein. The animals were ventilated with a small animal respirator (UGO BASILE 7025, 70 breaths/min, 1 ml/stroke/100 g).
  • a small animal respirator UGO BASILE 7025, 70 breaths/min, 1 ml/stroke/100 g.
  • a pressure transducer Physiological Pressure Transducer, MICRON INSTRUMENT MP-15
  • COULBOURN INSTRUMENT 572-25 an amplifier
  • COULBOURN INSTRUMENT R14-18 The rate of bronchoconstriction was measured as an increase in lung overflow with a bronchospasm transducer (UGO BASILE 7020) from a side arm off the tracheal cannula, and expressed as a percentage of maximum broncoconstriction obtained by clamping off the tracheal cannular.
  • Test compounds or vehicle (0.5% DMSO) were administered through the cannula into the jugular vein and ovalbumin (1.0 mg/kg, i.v.) was administered 10 minutes later. Bronchoconstriction response was compared to that obtained with control group treated with vehicle. Percent inhibition was calculated for each dose. If necessary, log dose-response curves were generated and the ID 50 values were determined by regression analysis. The results are presented in Table 3.
  • Pharmacology Example 4 The aeroallergen-induced bronchial infiltration of eosinophils in the bronchoalveolar lavage fluid.
  • the guinea pigs received either vehicle or compounds suspended in 1% acacia by oral garage.
  • the trachea was cannulated with an 18-gauge stainless steel feeding tube; 20 ml/kg of prewarmed (37° C.) physiological saline was instilled and the BALF was gently withdrawn.
  • BALF (amounting to 60-80% of the saline infused) was transferred to a 10 ml vacutainer containing 0.10 ml of 15% EDTA solution and centrifugated at 2400 rpm for 10 min.
  • the supernatant was poured off, and the cell pellet was suspended in physiological saline equal to the ratio of BALF recovered (ml) and physiological saline instilled in the lungs (ml), multiplied by two.
  • mice PAF given I.V. (10 ⁇ g/kg) to mice causes an immediate hypotensive shock leading to death in 1 hour or less.
  • Compounds were given intraperitoneally (dose of compounds : 10 mg/kg) at 2 minutes before the PAF challenge. Animals alive after 2 hours were counted and the activity of test compounds expressed as % survival corrected for any control (saline treated) animals which survived the PAF challenge. The results are presented in Table 5.

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US20030225052A1 (en) * 2002-03-29 2003-12-04 Kristian Stromgaard Analogs of terpene trilactones from Ginkgo biloba and related compounds and uses thereof
US6693091B2 (en) 2002-03-29 2004-02-17 The Trustees Of Columbia University In The City Of New York Analogs of terpene trilactones from Ginkgo biloba for bioorganic and imaging studies
WO2005046829A2 (en) * 2003-11-12 2005-05-26 The Trustees Of Columbia University In The City Of New York Separation of ginkgolides and bilobalide from g. biloba
US20050119336A1 (en) * 2003-08-27 2005-06-02 Koji Nakanishi Synthesis of derivatives of ginkgolide C
US6936285B1 (en) * 1997-12-03 2005-08-30 Societe De Conseils De Recherches D'application Scientifiques (S.C.R.A.S. Use of Ginkgo biloba extracts for preparing a medicine
US7078434B1 (en) 1999-08-12 2006-07-18 Societe De Conseils De Recherches Et D'applications Scientifiques Sas Use of Ginkgo extract
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US20080306145A1 (en) * 2004-11-23 2008-12-11 The Trustees Of Columbia University In The City Of New York Preparation Of Ginkgolide And F-Seco-Ginkgolide Lactols
US20090156668A1 (en) * 2004-03-19 2009-06-18 The Trustees Of Columbia University In The City Of New York Ginkgolide Compounds, Compositions, And Extracts, And Uses Thereof
US20090221019A1 (en) * 2005-06-22 2009-09-03 Koji Nakanishi Core-Modified Terpene Trilactones From Ginkgo Biloba Extract and Biological Evaluation Thereof
US20100056602A1 (en) * 2003-05-30 2010-03-04 Ranbaxy Laboratories Limited Substituted Pyrrole Derivatives And Their Use As HMG-CO Inhibitors
US20110064662A1 (en) * 2007-10-31 2011-03-17 Riken Kit for producing molecular probe for pet screening for drug discovery
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US20090118520A1 (en) * 2005-11-08 2009-05-07 Ranbaxy Laboratories Limited Process for preparation of (3r, 5r)-7-[2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-[(4-hydroxy methyl phenyl amino) carbonyl]-pyrrol-1-yl]-3,5-dihydroxy-heptanoic acid hemi calcium salt
US20080287690A1 (en) * 2005-11-08 2008-11-20 Ranbaxy Laboratories Limited Process For (3R, 5R)-7-[2-(4-Fluorophenyl)-5-Isopropyl-3-Phenyl-4- [(4-Hydroxy Methyl Phenyl Amino) Carbonyl]-Pyrrol-1-Yl]-3,5-Dihydroxy-Heptanoic Acid Hemi Calcium Salt
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HU9601295D0 (en) 1996-07-29
JPH09506107A (ja) 1997-06-17
CN1050132C (zh) 2000-03-08
BR9408463A (pt) 1997-08-26
JP3187838B2 (ja) 2001-07-16
CA2177736A1 (en) 1995-07-06
KR950018009A (ko) 1995-07-22
CN1139435A (zh) 1997-01-01
HUT74579A (en) 1997-01-28
EP0737195A1 (en) 1996-10-16
PL315174A1 (en) 1996-10-14
WO1995018131A1 (en) 1995-07-06
AU1426095A (en) 1995-07-17
KR0136986B1 (ko) 1998-04-25

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